Fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine) is an antidepressant drug which is disclosed, for example, in U.S. Pat. Nos. 4,314,081 and 4,626,549. The action of fluoxetine is based on its capacity to selectively inhibit the uptake of serotonin by the neurons in the central nervous system. Fluoxetine is indicated in the U.S. and many other countries for the treatment of depression, obsessive-compulsive disorder, and bulimia.
In the U.S., the currently available pharmaceutical forms for fluoxetine, in the form of the hydrochloride salt, include capsules and a solution. A tableted formulation for compounds of the fluoxetine type is also contemplated in U.S. Pat. No. 4,314,081 (column 16, lines 52-55). More recently, a dispersible tablet has been disclosed (see EPO Patent application publication 693,281). A sustained release formulation of fluoxetine is claimed in U.S. Pat. No. 4,847,092. Tablets of serotonin uptake inhibitors which are coated to delay absorption and disintegration to "provide a sustained action over a longer period" are generally contemplated in U.S. Pat. No. 4,444,778 (column 6, line 10 et seq.). Formulations of R-fluoxetine are generally contemplated in WO 92/13452 (controlled release and sustained release--page 19) and U.S. Pat. No. 5,356,934 (column 4). Similar teaching for S-fluoxetine are found in U.S. Pat. No. 5,104,899.
Enteric pharmaceutical formulations are manufactured in such a way that the product passes unchanged through the stomach of the patient, and dissolves and releases the active ingredient quickly when it leaves the stomach and enters the small intestine. Such formulations have long been used, and conventionally are in tablet or pellet form, where the active ingredient is in the inner part of the tablet or pellet and is enclosed in a film or envelope, the "enteric coating", which is insoluble in acid environments, such as the stomach, but is soluble in near-neutral environments such as the small intestine.
Certain difficulties arose in preparing conventional enteric formulations of fluoxetine. In particular, fluoxetine was found to react with many enteric coatings to form a slowly- or even insoluble coating. Similar reactions with enteric coatings have been observed with other drugs--duloxetine, nortriptyline, desipramine, sertraline and paroxetine.
Duloxetine, undergoing clinical evaluation as a candidate antidepressant, is (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, and is commonly used as its hydrochloride salt. An enteric coated formulation of duloxetine is claimed in U.S. Pat. No. 5,508,276, to avoid acid degradation of the compound in the stomach.
It has been observed that, because of fluoxetine's long half life, dosing regimens other than daily dosing are effective, especially for maintenance dosing. For example, Burke, et al., Psychopharmacol. Bull., 31(3), 524 (1995) reported that 60 mg of fluoxetine hydrochloride given once per week was as effective as 20 mg per day during maintenance therapy (i.e., after eight weeks of daily dosing). Montgomery, et al., Eur. Arch. Psychiatry Clin. Neuroscience, 244(4), 211 (1994) reported that 120 mg of fluoxetine dosed biweekly was ineffective for treating recurrent brief depression. Twenty milligrams per week of fluoxetine were advocated by Benazzi, et al., Pharmacopsychiatry, 27(6), 246 (1994), for reducing sexual dysfunction side effects. While the above studies employed single or multiple 20 mg capsules to provide the indicated therapy, 60 mg capsules of fluoxetine hydrochloride are available in, e.g., South Africa for treating bulimia.
Because of fluoxetine's long half life, there has not been any perceived need to actually prepare a fluoxetine formulation providing a longer payout. While these higher doses of fluoxetine have been shown to be efficacious, there can be associated side effects, such as nausea, presumably due to local irritation or the increased plasma levels shortly after dosing. Therefore, it has now been appreciated that a formulation having higher doses of fluoxetine (e.g., 60-120 mg) which blunts the initial release of fluoxetine will have clinical advantages, i.e., not only will such formulations provide convenient and effective one per week dosing, but will have an advantage of less side effects.
It is therefore desirable to have a formulation that could be used to provide a convenient single dose for maintenance therapy suggested by the above articles without providing an increase in undesirable side effects.
The present invention was created through efforts to solve the above and other problems, and provides a superior enteric formulation of fluoxetine.